Members of the ErbB family of transmembrane receptor tyrosine kinases are important mediators of cell growth, cell differentiation, cell migration, and apoptosis. The receptor family includes four distinct members, including epidermal growth factor receptor (EGFR or ErbB1), HER2 (ErbB2 or p185), HER3 (ErbB3) and HER4 (ErbB4 or tyro2).
HER2 was originally identified as the product of the transforming gene from neuroblastomas of chemically treated rats. HER2 overexpression has been validated as tumorigenic both in vitro (Di Fiore et al., 1987, Science 237(4811):178-82; Hudziak et al., 1987, PNAS 84(20):7159-63; Chazin et al., 1992, Oncogene 7(9):1859-66) and in animal models (Guy et al., 1992, PNAS 89(22):10578-82). Amplification of the gene encoding HER2 with consequent overexpression of the receptor occurs in breast and ovarian cancers and correlates with a poor prognosis (Slamon et al., 1987, Science 235(4785):177-82; Slamon et al., 1989, Science 244:707-12; Anbazhagan et al., 1991, Annals Oncology 2(1):47-53; Andrulis et al., 1998, J Clinical Oncology 16(4):1340-9). Overexpression of HER2 (frequently but not necessarily due to gene amplification) has also been observed in other tumor types including gastric, endometrial, non-small cell lung cancer, colon, pancreatic, bladder, kidney, prostate and cervical (Scholl et al., 2001, Annals Oncology 12 (Suppl. 1):581-7; Menard et al., 2001, Ann Oncol 12(Suppl 1):515-9; Martin et al., 2014, Future Oncology 10:1469-86).
Herceptin® (trastuzumab) is a humanized monoclonal antibody that binds to the extracellular domain of HER2 (Carter et al. 1992, PNAS 89:4285-9 and U.S. Pat. No. 5,821,337). Herceptin® received marketing approval from the Food and Drug Administration on Sep. 25, 1998 for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Although Herceptin® is a breakthrough in treating patients with HER2-overexpressing breast cancers that have received extensive prior anti-cancer therapy, segments of patients in this population fail to respond, respond only poorly or become resistant to Herceptin® treatment.
Kadcyla® (trastuzumab-DM1 or T-DM1) is an antibody drug conjugate consisting of trastuzumab conjugated to the maytansinoid agent DM1 via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate) (Lewis et al., 2008, Cancer Res. 68:9280-90; Krop et al., 2010, J Clin Oncol. 28:2698-2704; U.S. Pat. No. 8,337,856). Kadcyla® received marketing approval from the Food and Drug Administration on Feb. 22, 2013 for the treatment of HER2 positive metastatic breast cancer in patients who had been previously treated with Herceptin® and a taxane drug and became Herceptin® refractory. Like seen with Herceptin®, there are segments of the patients in the HER2-overexpressing breast cancer population that do not experience successful long term therapy with Kadcyla®.
Therefore, there is a significant clinical need for developing further HER2-directed cancer therapies for those patients with HER2-overexpressing tumors or other diseases associated with HER2 overexpression that do not respond, respond poorly or become resistant to Herceptin® and/or Kadcyla® treatment.